Method of determing absolute configuration of chiral compound

ABSTRACT

The absolute configuration of a chiral compound is determined by (i) coordinating the chiral compound to a metalloporphyrin having a carbon chain-crosslinked porphyrin dimer structure in which one of the two porphyrin rings has at least one ethyl or substituent bulkier than ethyl at at least one of the second peripheral carbon atoms from the carbon atom at the carbon chain crosslink site, and (ii) analyzing the resultant coordination compound by circular dichroism spectrophotometry to determine the absolute configuration of the asymmetric carbon based on the sign of the Cotton effect. The chiral compound has an asymmetric carbon bonded to a basic group capable of coordinating to the metal of the other porphyrin ring of the metalloporphyrin dimer or an asymmetric carbon atom adjacent to the carbon atom bonded to the basic group.

TECHNICAL FIELD

[0001] The present invention relates to a method for determining theabsolute configuration of chiral compounds.

BACKGROUND ART

[0002] Conventionally, there have been attempts to determine theabsolute configuration of external ligands based on the induced Cottoneffects revealed by the analysis of circular dichroism (CD)spectrophotometry. For example, the following are reported:

[0003] (1) E. Yashima, T. Matsushima, and Y. Okamoto (J. Am. Chem. Soc.,1997, 119, 6345-6359) report on polymers forming a helical structure inthe presence of a chiral compound and describe that there is a goodcorrelation between the sign of the Cotton effect in the circulardichroism spectra induced by the ligand (chiral compound) and theabsolute configuration of the ligand.

[0004] However, since the helical structure is induced by the ion pairformed between the carboxylate group of the polymer side chain and theammonium group of the ligand, this method can be used for typicalmonoamines and aminoalcohols but is not applicable to alcohols.

[0005] (2) X. Huang, B. H. Rickmann, B. Borhan, N. Berova, and K.Nakanishi (J. Am. Chem. Soc., 1998, 120, 6185-6186) report on circulardichroism induced in a long chain-crosslinked porphyrin diner by achiral ligand. There is a correlation between the sign of the Cottoneffect and the absolute configuration of the ligand. In this system,however, circular dichroism is induced only when one ligand molecule isconcurrently coordinated to two porphyrin units. Therefore, this methodis useful only for bifunctional compounds such as diamines andaminoalcohols.

[0006] (3) M. Takeuchi, T. Imada, and S. Shinkai (Bull. Chem. Soc.,Jpn., 1998, 71, 1117-1123) report that a porphyrin dimer having aphenylboronic acid unit exhibits circular dichroism in the presence of avariety of sugars.

[0007] This method is applicable only to polyols (polyalcohols) whichform a chemical bond with boronic acid, and it is not a method fordirectly determining the absolute configuration around a specificasymmetric center.

[0008] (4) H. Tsukube, M. Hosokubo, M. Wada, S. Shinoda, and H. Tamiaki(J. Chem. Soc., Dalton Trans., 1999, 11-12) report that atris(β-diketonato) lanthanide complex exhibits circular dichroism in thepresence of chiral amino alcohols. In this system, however, monoaminesor monoalcohols do not induce chirality.

[0009] (5) S. Zahn, and J. W. Canary (Org. Lett., 1999, 1, 861-864)report that the absolute configuration of amino acids and aminoalcoholscan be determined based on the circular dichroism of their coppercomplexes.

[0010] However, this method is applicable only to bidentate amino acidsand aminoalcohols and can not be used for monoamines or monoalcohols.

[0011] As is clear from the above, there have been no reports about amethod for determining the absolute configuration of chiral compoundshaving a wide variety of basic groups, such as monoalcohols.

[0012] The X-ray diffraction method is known as a method for determiningthe absolute configuration of chiral compounds. However, there is alimitation in that this method is applicable only to crystallinecompounds.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013]FIG. 1 shows the circular dichroism of a zinc porphyrin dimerinduced by a chiral amine.

[0014]FIG. 2 is a schematic diagram showing the mechanism of asymmetricinduction in a zinc porphyrin dimer.

[0015]FIG. 3 illustrates the moment directions of the maximum absorptionband of a porphyrin dimer.

[0016]FIG. 4 shows CD spectra obtained using(R)-(−)-1-cyclohexylethylamine in the Example.

[0017]FIG. 5 shows CD spectra obtained using (R)-(−)-phenylethanol inthe Example.

DISCLOSURE OF THE INVENTION

[0018] The principal object of the present invention is to overcome thelimits and problems of the prior art and provide a novel general-purposemethod for precisely and easily determining the absolute configurationof chiral compounds having a wide variety of basic groups.

[0019] The present invention provides the following methods fordetermining the absolute configuration of chiral compounds:

[0020] 1. A method for determining the absolute configuration of achiral compound which comprises:

[0021] coordinating the chiral compound to a metalloporphyrin, themetalloporphyrin having a carbon chain-crosslinked porphyrin dimerstructure in which one of the two porphyrin rings has at least one ethylor substituent bulkier than ethyl at at least one of the secondperipheral carbon atoms from the carbon atom at the carbon chaincrosslink site,

[0022] the chiral compound having an asymmetric carbon bonded to a basicgroup capable of coordinating to the metal of the other porphyrin ringof the metalloporphyrin dimer or an asymmetric carbon atom adjacent tothe carbon atom bonded to the basic group; and

[0023] analyzing the resultant coordination compound by circulardichroism spectrophotometry to determine the absolute configuration ofthe asymmetric carbon of the chiral compound based on the sign of theCotton effect.

[0024] 2. The method according to item 1 wherein the ethyl orsubstituent bulkier than ethyl is 1) a hydrocarbon group having at least2 carbon atoms, 2) an oxygen-containing substituent, 3) anitrogen-containing substituent, 4) a halogen atom, or 5) a halogenatedhydrocarbon group.

[0025] 3. The method according to item 1 wherein the chiral compoundis 1) a primary amine, 2) a secondary amine, 3) a primary diamine, 4) asecondary diamine, 5) a monoalcohol, or 6) an aminoalcohol.

[0026] 4. The method according to item 1 or 3 wherein themetalloporphyrin is a compound represented by the following formula (I):

[0027]{μ{{5,5′-(ethane-1,2-diyl)bis[2,3,7,8,12,13,17,18-octaethyl-21H,23H-porphyrinato](4-)}-κN²¹,κN²², κN²³, κN²⁴, κN^(21′), κN^(22′), κN^(23′), κN^(24′)}}dizinc.

[0028] The present invention uses circular dichroism (CD)spectrophotometric analysis as described above. In this analysis, thesign of the induced Cotton effect is determined by the absoluteconfiguration of the asymmetric carbon of the external ligand. Accordingto the CD exciton-chirality method (Harada, N.; Nakanishi, K.; CircularDichroic Spectroscopy-Exciton Coupling in Organic Stereochemistry;University Science Books; Mill Valley, 1983., Nakanishi, K.; Berova, N.In Circular Dichroism; Principles and Applications; Woody, R., Ed; VCHPublishers; New York, 1994; pp. 361-398), a clockwise orientation of twointeracting electronic transition moments produces positive chirality,while a counterclockwise orientation leads to negative chirality.

[0029] The present invention was accomplished based on the finding thatthere is a specific correlation between the sign of the Cotton effectand the absolute configuration of the asymmetric carbon of a chiralcompound (R-isomer or S-isomer) as a ligand.

[0030] The basic principle of this determination of the absoluteconfiguration is described below with reference to the case of zincporphyrin represented by formula (I):

[0031]{μ{{5,5′-(ethane-1,2-diyl)bis[2,3,7,8,12,13,17,18-octaethyl-21H,23H-porphyrinato](4-)}-κN²¹,κN²², κN²³, κN²⁴, κN^(21′), κN^(22′), κN^(23′), κN^(24′)}}dizinc.

[0032] This zinc porphyrin has a porphyrin dimer structure in which oneof the porphyrin rings has two ethyl groups (—CH₂CH₃) each bonded to thesecond peripheral carbon atoms (b), (b) from the carbon atom (a) at thecrosslink site crosslinked by an ethylene chain (—CH₂—CH₂—).

[0033] Of course, in the present invention, it is also possible to use ametalloporphyrin which has, in place of the above ethylene chain, acarbon chain having a suitable number of carbon atoms (preferably, aC₂₋₃ carbon chain) such as an alkylene chain or the like, themetalloporphyrin ring having at least one bulky substituent in place ofat least one of the ethyl groups bonded to the porphyrin ring at thesites (b), (b).

[0034] The present inventors already found that a zincoctaethylporphyrin dimer (ZnD) as above undergoes a conformationalchange from syn to anti upon coordination of an alcohol or an amine suchas those represented by the following formulas:

[0035] Further, the inventors newly found that upon coordination of achiral alcohol or a chiral amine, asymmetry is induced in the anticonformer, whereby circular dichroism is exhibited as shown in FIG. 1.The mechanism of asymmetric induction is illustrated in FIG. 2. Thus itcan be understood that the porphyrins' orientation is twisted by thesteric hindrance between the ethyl group (Et) of the porphyrin and thebulkiest substituent (X) bonded to the α carbon of the ligand, and theexciton interaction between the porphyrin rings produces circulardichroism.

[0036] The correlation between the absolute configuration (R-isomer orS-isomer) of a ligand and the sign of the Cotton effect is demonstrated,for example, in Table 1. Table 1 indicates that there is acorrespondence between the sign of the Cotton effect and the stericconfiguration around the α carbon of amino or hydroxyl groups. As shownin FIG. 1, the peak occurring at a shorter wavelength shows the secondCotton effect, whereas the peak at a longer wavelength shows the firstCotton effect. The signs at the peaks may be positive or negative. Forexample, in the case of 1-phenylethylamine shown in FIG. 1, when theabsolute configuration is (R), the second Cotton effect is positive andthe first Cotton effect is negative. When the absolute configuration is(S), these signs are reversed. That is, when the first Cotton effect ispositive, the absolute configuration of the chiral compound is (S). Whenthe first Cotton effect is negative, the absolute configuration of thechiral compound is (R). Table 1 shows that this correspondence exists inmany chiral compounds. These results prove that the above assumptionabout the mechanism of chirality induction is correct. Based on thiscorrespondence, it is also possible to determine the absoluteconfiguration of chemical compounds whose absolute configuration isunknown. TABLE 1 Assignment of absolute configuration of chiral aminesand alcohols Second Absolute Cotton First cotton configuration (B_(⊥)(B_(II) Ligand and sign of ligand transition) transition) 2-Buthanol(R)-(−) + − (S)-(+) − + 1-Phenylethanol (R)-(+) + − (S)-(−) − +2-Buthylamine (R)-(−) + − (S)-(+) − + 1-Phenylethylamine (R)-(+) + −(S)-(−) − + 1-(1-Naphthyl)ethylamine (R)-(+) + − (S)-(−) − +1,2-Diaminocyclohexane (1R,2R)-(−) + − 1-Amino-2-propanol (R)-(−) + −(S)-(+) − + 2-Amino-4-methyl-1- (R)-(−) + − pentanol (S)-(+) − +1-Cyclohexylethylamine (R)-(−) + − (S)-(+) − + N-methyl-1 (R)-(+) + −phenylethylamine (S)-(−) − + 2-Methyl-1-butylamine (S)-(−) − +Bornylamine (1R,2S)-(+) − + 1,2-Diphenylethylene- (1R,2R)-(+) + −diamine (1S,2S)-(−) − +

[0037] In Table 1, the B_(II) transition is a transition occurring whenthe moments of two porphyrin rings are aligned in the direction ofbonding the porphyrin rings and the resulting absorption band is B-band.The B_(⊥) transition is a transition occurring when the moments of twoporphyrin rings are in directions perpendicular to the direction ofbonding the porphyrin rings and the resulting absorption band is B-band(see the solid line in FIG. 3). In both the B_(II) transition and theB_(⊥) transition, the directions of moments of the two porphyrin ringsof a chiral porphyrin dimer are slightly misaligned with respect to eachother, as compared to the achiral porphyrin dimer (see the dotted linein FIG. 3).

[0038] As described above with respect to zinc porphyrin, the inventionmakes it possible to determine the absolute configuration of theasymmetric carbon of chiral compounds.

[0039] The metalloporphyrin used in the method of the invention has acarbon-chain crosslinked porphyrin dimer structure in which one of thetwo porphyrin rings has ethyl or substituent bulkier than ethyl at atleast one of the second peripheral carbon atoms from the carbon atom atthe carbon chain crosslink site (i.e., the carbon atom bonded to thecrosslinking carbon chain, on one of the porphyrin rings).

[0040] The ethyl or substituent bulkier than ethyl means a substituentwhose volume is as large as or larger than ethyl. Examples of suchsubstituents include 1) hydrocarbon groups having at least 2 carbonatoms such as ethyl, propyl, butyl and the like, 2) oxygen-containingsubstituents such as ester groups (e.g., methyl ester, ethyl ester),carboxymethyl and the like, 3) nitrogen-containing substituents such asamino, amide, 2-aminoethyl and the like, 4) halogen atoms such as —Cl,Br—, —F and the like, and 5) halogenated hydrocarbon groups such aschloroethyl and the like. The same or different substituents may bebonded to a metalloporphyrin.

[0041] Any of a variety of metal porphyrin compounds can be used as themetalloporphyrin as long as the metal is a 6-coordinate metal. Suchmetals are not limited to zinc but also include Fe, Mn, Ru, etc. The twometals of the dimer may be the same or different.

[0042] The metalloporphyrin used in the present invention can besynthesized by known methods (e.g., Japanese Unexamined PatentPublication No. 255790/1999). The use of zinc porphyrin is especiallypreferred in the present invention.

[0043] The chiral compound whose absolute configuration can bedetermined by the method of the invention is, basically, a compoundhaving an asymmetric carbon bonded to a basic group capable ofcoordinating to the metal on the porphyrin ring of said metalloporphyrindimer or an asymmetric carbon adjacent to the carbon atom bonded to saidbasic group (i.e., an asymmetric carbon bonded to the carbon atom havingthe basic group). In the metalloporphyrin dimer, one porphyrin ring hasat least one ethyl or substituent bulkier than ethyl and the otherporphyrin ring bonded thereto has a metal.

[0044] Representative examples of such basic groups are amino andhydroxyl. More specifically, the chiral compound whose absoluteconfiguration can be determined by the method of the present inventionis a compound which forms a ligand for a metalloporphyrin.Representative examples of chiral compounds are 1) primary amines, 2)secondary amines, 3) primary diamines, 4) secondary diamines, 5)monoalcohols, and 6) aminoalcohols.

[0045] For example, all the compounds listed in Table 1 from 2-buthanolto N-methyl-1-phenylethylamine correspond to chiral compounds having anasymmetric carbon bonded to a basic group capable of coordinating to themetal of the porphyrin ring. 2-methyl-1-butylamine corresponds to achiral compound having an asymmetric carbon adjacent to the carbon atombonded to the coordinative basic group. With respect to compounds having2 or more asymmetric carbons such as bornylamine and diamine shown inTable 1, the absolute configuration of the asymmetric carbon bonded tothe amino group coordinated to the metal of the metalloporphyrin can bedetermined.

[0046] In the present invention, the chiral compound capable of forminga ligand for a metalloporphyrin is coordinated to the metalloporphyrin,preferably in a non-ligand-forming solvent, and the resultingcoordination compound is analyzed by CD spectrophotometry.

[0047] That is, the new method of the present invention for determiningthe absolute configuration of a variety of chiral compounds capable ofcoordination to metalloporphyrins comprises analyzing a mixed sample ofa chiral compound and a metalloporphyrin in a non-ligand solvent, bycircular dichroism (CD) spectrophotometry. According to this method, theabsolute configuration of chiral compounds can be directly observedwithout the need to derive any specifically modified compounds, and thechirality of the carbon atom directly bonded to the ligand-forming groupor a carbon atom adjacent to the carbon atom can be determined.

[0048] Representative examples of non-ligand solvents includehalogenated aliphatic hydrocarbons such as chloroform (CHCl₃),dichloride methane (CH₂Cl₂), dichloride ethane (CH₂ClCH₂Cl),tetrachloride ethane (CHCl₂CHCl₂), carbon tetrachloride (CCl₄) and thelike, and aliphatic hydrocarbons such as hexane, heptane and the like.

[0049] In the method of the present invention, samples to be analyzed byCD spectrophotometry can be prepared, for example, in the followingmanner:

[0050] A chiral compound and a metalloporphyrin are dissolved in saidsolvent. The concentrations of the chiral compound and themetalloporphyrin are not critical. Generally, the concentration of thechiral compound should be 10⁻⁴ mol/l or higher, and the concentration ofthe metalloporphyrin 10⁻⁶ mol/l or higher. Their concentrations cansuitably be selected from the above ranges in accordance with the typeof solvent used, etc.

[0051] In the case of the metalloporphyrin of formula (1), the minimumconcentrations of chiral compounds required for observing sufficientCotton effects are as follows: primary acyclic monoamines preferablyhave a minimum concentration of about 10⁻³ mol/l, cyclic aromaticmonoamines about 10⁻⁴ mol/l, secondary amines about 10⁻⁴ mol/l, diaminesabout 10⁻³ mol/l and aminoalcohols about 10⁻³ mol/l. Preferably, theminimum concentration of monoalcohols required for observing sufficientCotton effects is about 10⁻¹ mol/l and the temperature is −80° C.

[0052] The following cases 1-5 can be mentioned as examples.

[0053] [Case 1]

[0054] The absolute chirality of primary monoamines can preferably bedetermined when the minimum concentration thereof in chloroform,dichloromethane, carbon tetrachloride, tetrachloroethane, hexane orheptane is adjusted to about 10⁻⁴ mol/l to 10⁻³ mol/l and theconcentration of the metalloporphyrin of formula (I) is about 10⁻⁶mol/l. Examples of primary monoamines include 2-butylamine,1-phenylethylamine, 1-(1-naphtyl)ethylamine, 1-cyclohexylethylamine,2-methyl-1-butylamine, and[endo-(1R)-1,7,7-trimethylbicyclo[2,2,1]heptan-2-amine].

[0055] [Case 2]

[0056] The absolute chirality of secondary monoamines can preferably bedetermined when the minimum concentration thereof in chloroform,dichloromethane, carbon tetrachloride, tetrachloroethane, hexane orheptane is adjusted to about 10⁻⁴ mol/l and the concentration of themetalloporphyrin of formula (I) is about 10⁻⁶ mol/l. Examples ofsecondary monoamines include N-methyl-1-phenylethylamine.

[0057] [Case 3]

[0058] The absolute chirality of diamines can preferably be determinedwhen the minimum concentration thereof in chloroform, dichloromethane,carbon tetrachloride, tetrachloroethane, hexane or heptane is adjustedto about 10⁻³ mol/l and the concentration of the metalloporphyrin offormula (I) is about 10⁻⁶ mol/l. Examples of diamines include1,2-diphenylethylenediamine and 1,2-diaminocyclohexane.

[0059] [Case 4]

[0060] The absolute chirality of aminoalcohols can preferably bedetermined when the minimum concentration thereof in chloroform,dichloromethane, carbon tetrachloride, tetrachloroethane, hexane orheptane is adjusted to about 10⁻³ mol/l and the concentration of themetalloporphyrin of formula (I) is about 10⁻⁶ mol/l. Examples ofaminoalchols include 1-amino-2-propanol and 2-amino-4-methyl-1-pentanol.

[0061] [Case 5]

[0062] The absolute chirality of monoalcohols can preferably bedetermined when the minimum concentration thereof is adjusted to about10⁻¹ mol/l and the concentration of the metalloporphyrin of formula (I)is about 10⁻⁶ mol/l in dichloromethane or hexane at −80° C. Examples ofmonoalcohols include 2-butanol and 1-phenylethanol.

[0063] The present invention enables precise and easy determination ofthe absolute configuration of chiral compounds having a wide variety ofbasic groups bonded thereto. That is, the method of the invention canprecisely and easily determine the absolute configuration of the chiralcompounds having an asymmetric carbon directly bonded to a coordinativebasic group or an asymmetric carbon adjacent to the carbon atom bondedto the basic group. More specifically, the method of the presentinvention achieves the following excellent effects:

[0064] 1) The absolute chirality of various optionally active compoundscan be directly observed.

[0065] 2) Only trace amounts of samples, i.e., metalloporphyrin (at thelevel of μg) and chiral compounds (amines (μg), alcohols (mg)) areneeded.

[0066] 3) Since no chemical change occurs, the samples can be recoveredeasily, if necessary.

[0067] 4) Determination of absolute chirality is very fast. Preparationof the samples and measurement of the CD spectra can be done in 10minutes.

[0068] 5) The detection of Cotton effects is usually carried out in theregion of 400 to 450 nm, while most chiral compounds have absorptions upto 400 nm. Therefore, a wide variety of compounds can be analyzed.

[0069] 6) The chiral compounds can be used without the need to deriveany specifically modified compounds.

[0070] 7) The absolute chirality of non-crystalline compounds can bedetermined.

BEST MODE FOR CARRYING OUT THE INVENTION

[0071] The present invention will be described below in further detailwith reference to an Example.

EXAMPLE 1

[0072] A CH₂Cl₂ solution containing about 10⁻⁶ mol/l of zinc porphyrinof formula (I) and about 10⁻⁴ mol/l of (R)-(−)-1-cyclohexylamine wasprepared in a 3 ml cell, and the circular dichroism spectra wereobserved in the region of 350 nm to 500 nm at room temperature. FIG. 4shows the results.

[0073] The absolute configuration of a chiral compound is determinedfrom the sign of the first Cotton effect at a longer wavelength. Fromthe negative sign of the first Cotton effect as shown in FIG. 4, theabsolute configuration of (R)-(−)-1-cyclohexylethylamine was confirmedto be (R).

[0074] Similarly, a CH₂Cl₂ solution containing about 10⁻⁶ mol/l of thezinc porphyrin and about 10⁻¹ mol/l of (R)-(−)-1-phenylethanol wasprepared in a 3 ml cell, and the circular dichroism spectra wereobserved in the region of 350 nm to 500 nm at −80° C. FIG. 5 shows theresults.

[0075] In this case also, the sign of the first Cotton effect wasnegative. Thus the absolute configuration of the chiral compound wasconfirmed to be (R).

[0076] The method of the present invention determines the absoluteconfiguration of chiral compounds in the manner described above. Theeffectiveness of this method was also confirmed for the assignment ofthe absolute configuration of chiral amines and alcohols as shown inTable 1.

1. A method for determining the absolute configuration of a chiralcompound which comprises: coordinating the chiral compound to ametalloporphyrin, the metalloporphyrin having a carbon chain-crosslinkedporphyrin dimer structure in which one of the two porphyrin rings has atleast one ethyl or substituent bulkier than ethyl at at least one of thesecond peripheral carbon atoms from the carbon atom at the carbon chaincrosslink site, the chiral compound having an asymmetric carbon bondedto a basic group capable of coordinating to the metal of the otherporphyrin ring of the metalloporphyrin dimer or an asymmetric carbonatom adjacent to the carbon atom bonded to the basic group; andanalyzing the resultant coordination compound by circular dichroismspectrophotometry to determine the absolute configuration of theasymmetric carbon of the chiral compound based on the sign of the Cottoneffect.
 2. The method according to claim 1 wherein the ethyl orsubstituent bulkier than ethyl is 1) a hydrocarbon group having at least2 carbon atoms, 2) an oxygen-containing substituent, 3) anitrogen-containing substituent, 4) a halogen atom, or 5) a halogenatedhydrocarbon group.
 3. The method according to claim 1 wherein the chiralcompound is 1) a primary amine, 2) a secondary amine, 3) a primarydiamine, 4) a secondary diamine, 5) a monoalcohol, or 6) anaminoalcohol.
 4. The method according to any one of claims 1 to 3wherein the metalloporphyrin is a compound represented by the followingformula (I):

{μ{{5,5′-(ethane-1,2-diyl)bis[2,3,7,8,12,13,17,18-octaethyl-21H,23H-porphyrinato](4-)}-κN²¹,κN²², κN²³, κN²⁴, κN^(21′), κN^(22′), κN^(23′), κN^(24′)}}dizinc.